Published on Web 07/22/2008

Catalytic Enantioselective Pudovik Reaction of Aldehydes and Aldimines with

Tethered Bis(8-quinolinato) (TBOx) Aluminum Complex
Joshua P. Abell and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received May 22, 2008; E-mail: yamamoto@uchicago.edu

The addition of dialkylphosphites to carbonyl compounds to Scheme 1. Synthesis of (R)-TBOxAlCl

generate R-hydroxyphosphonates, known as the Pudovik reaction,
is a powerful and direct method for construction of C-P bonds.
With the potential to synthesize biologically important phospho-
derivatives of R-hydroxycarboxylic acids, this reaction has
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received deserved attention lately to make the process highly

enantioselective.1 To date several organocatalysts including
Cinchona alkaloids2 and chiral phosphoric acids,3 Lewis acids
including titanium,4 late transition metals,5 aluminum6a
SALALEN,6b SALEN,7 SALAN,7 BINOL,8 and chiral vanadium
Table 1. Reaction Optimization
catalyst9 have been utilized for this reaction. Unfortunately, these
catalysts typically require high catalyst loading and long reaction
times, usually g5 mol % or greater and several days.
Due to the recent success using the ligand 1 developed in our
laboratory,10 we envisaged that our ligand, when complexed with
aluminum, could prove to be a highly selective and active catalyst
entry R T(°C) yield (%)a ee (%)b
for the Pudovik reaction. With the chiral tethered bis(8-quinolinato)
(TBOxH) ligand in hand, complexation took place smoothly at room 1 Me RT 20 24
2 Et RT 18 23
temperature by addition of a solution of Et2AlCl (Scheme 1). This 3c Me RT 94 20
catalyst 2 was used under previously reported conditions; however, 4 Ph RT 48 <5
only low yields and enantioselectivities were observed (Table 1, 5d CH2CF3 RT 94 48
entries 1-4). With these positive results we set out to find a more 6 CH(CF3)2 RT 30 <5
7e CH2CF3 -15 27 50
reactive system.
8f CH2CF3 RT 93 65
While the actual mechanism has not been experimentally 9g CH2CF3 RT 94 78
confirmed, it is believed that the first step is deprotonation of a
the phosphite to generate a more highly nucleophilic species.1d Isolated yield after column chromatography. b Determined by HPLC
analysis. c 5.0 equiv of phosphite was employed. d Reaction was
The proton on the phosphite was found to be crucial for the completed after 1 h. e Reaction not complete after 24 h. f 1 mol %
enantioselectivity of the reaction.11 Using a more electron catalyst employed. g Hexanes used as solvent.
withdrawing alkyl group on the phosphite the yield could be
improved to synthetically useful levels. As shown in Table 1,
the bis(2,2,2-trifluoroethyl) phosphite increased the yield to 94% at the 5,5′-position of the quinoline ring led to a dramatic
and the enantioselectivity to 48% (entry 5).12 With efforts now increase in enantioselectivity (entry 2). Pleased with this result
focused on increasing the enantioselectivity, increasing the size we further examined other derivatives and found catalysts 4 and
of the alkyl group only decreased the yield and selectivity (entry 5 to be most reactive and selective (entries 3 and 4). Since there
6), possibly due to decreased nucleophilicity of the phosphite was no change in yield and enantioselectivites of the most
and increased steric environment. Decreasing the reaction selective catalysts, catalyst 4 was chosen for further examination.
temperature only decreased the reactivity while not increasing Having optimized reaction conditions, the substrate scope of
the enantioselectivity (entry 7). Interestingly, after screening the the reaction was explored (Table 3). It was found that electron
reaction conditions, decreasing the catalyst loading of the rich compared to electron poor aromatic aldehydes proved to
reaction increased the enantioselectivity while maintaining the be more reactive and selective (entries 6, 7, 9, 10). Aliphatic
same reactivity and yield (entry 8). This phenomenon was also aldehydes could also be used, further establishing the utility of
observed with the work of North in the enantioselective our system (entries 11,12). All reactions proceeded very quickly,
silylcyanation reaction13 and more closely related with Kee’s with high yields and enantioselectivity. Furthermore, the catalyst
hydrophosphonylation reaction.7 Furthermore, it was found that loading could be decreased to 0.5 mol % with essentially no
nonpolar solvents gave higher enantioselectivity, with hexanes loss in enantioselectivity or yield with slightly prolonged reaction
giving the highest reactivity and selectivity (entry 9). times (entries 1, 3, 7).
With the influence of the phosphite and solvent now estab- Upon further investigation of this ligand system with previ-
lished, the ligand structure was examined (Table 2). The ligand ously synthesized ligands by our group, it was found that the
structure was found to be highly influential on the enantiose- substitution at the 5,5′-position of the quinoline ring had a
lectivity of the product. Simply attaching a phenyl substituent dramatic increase on the rate of the reaction. To demonstrate
10.1021/ja803859p CCC: $40.75  2008 American Chemical Society J. AM. CHEM. SOC. 2008, 130, 10521–10523 9 10521
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Table 2. Catalyst Optimization Table 4. Aldimine Protection Group Screening

entry P yield (%)a ee (%)b

1 Boc trace ND
2 Bn 62 <5
3 Ph 35 15
4 DPPc 95 96
a
Isolated yield after column chromatography. b Determined by HPLC
analysis. c DPP ) diphenylphosphinoyl.

entry catalyst yield (%)a ee (%)b

Table 5. Aldimine Reaction Scopec
1 2 94 78
2 3 95 91
3 4 96 96
4 5 95 96
a
Isolated yield after column chromatography. b Determined by HPLC
analysis.
entry R yield (%)a ee (%)b
1 Ph 98 96
Table 3. Aldehyde Reaction Scoped
2 4-ClC6H4 85 90
3 4-BrC66H4 88 92
4 4-NO2C6H4 90 88
5 4-MeOC6H4 91 90
6 4-MeC6H4 92 96
entry R time (min) yield (%)a ee (%)b 7 3-MeOC6H4 93 98
8 2-MeC6H4 90 90
1 Ph 10 95 (94) 96 (95)c 9 2-MeC6H4 96 92
2 2-naphthyl 15 98 95 10 2-furyl 89 91
3 4-ClC6H4 15 94 (93) 95 (93)c 11 2-thienyl 93 94
4 4-BrC6H4 15 96 95
5 4-NO2C6H4 10 93 92 a
Isolated yield after column chromatography. b Determined by HPLC
6 4-MeOC6H4 10 93 97 analysis (see Supporting Information). c Absolute configuration
7 4-MeC6H4 5 94 (94) 94 (94)c determined by optical rotation in comparison with previously reported
8 3-MeOC6H4 20 93 95 R-amino phosphonic acid.
9 2-MeOC6H4 10 93 93
10 2-MeC6H4 5 95 95
11e c-hexyl 25 95 82
12e n-hexyl 20 91 82 as antifungal16 and antibacterial16 agents highly depends on the
absolute configuration of the R-carbon. To date only a few
a
Isolated yield after column chromatography. b Determined by HPLC examples of catalyzed hydrophosphonylation to aldimines with
analysis. c 0.5 mol % was employed in parentheses. d Absolute a direct C-P bond formation exist.12,17,18 Still improvements
configuration determined by X-ray analysis of entry 4. e Ee determined
after conversion to benzoate ester.
in the area of catalyst loading and reaction times can be made.
After screening several imines it was found that N-diphe-
nylphosphinoyl imines provided the highest enantioselectivity
Scheme 2. Ligand Competition Experiment
and yield (Table 4). N-Diphenylphosphinoyl imines have been
demonstrated previously as versatile electrophiles in a number
of asymmetric reactions.19 This labile nitrogen protection group
is easily cleaved in mildly acidic conditions.
Using the typical reaction conditions the substrate scope of
this reaction was established (Table 5). A variety of imines are
the difference in reactivity, the enantiopure 5,5′-substituted ligand well suited for this catalyst system including a number of
((R)-Al cat. 4) and an enantiopure unsubstituted oppositely subsituents and hetereoatoms. Electron rich aldimines showed
stereoconfigured ligand ((S)-Al cat. 2) were added in equal higher reactivity (entries 5-9), while electron poor aldimines
catalytic amounts to a reaction vessel and subjected to the typical showed slightly diminished reactivity but still high yields of the
reaction conditions (Scheme 2). It was found that the product protected amines (entries 2-4). This high enantioselection using
was favored for the substituted ligand in the same enantiose- both aldehydes and aldmines has been shown previously, albeit
lection as the same ligand alone. with longer reaction times and higher catalyst loadings.17
In light of the recent success with the simple synthesis of The use of optically active R-hydroxy- and R-aminophopho-
R-hydroxyphosphonates we expected that our aluminum catalyst nates to test for biological activity requires that the phosphorus
could also be applicable to other electrophiles and the natural moiety be deprotected to the free acid. Serveral reported
extension of aldehydes is aldimines. Synthesis of optically active procedures utilize either TMSBr,1,20 TMSCl, and NaI1,21 at room
R-aminophophonates has been the pursuit of several research temperature or BBr322 at elevated temperatures to deprotect the
groups.12,14 Their potential use as proteinase inhibtors15 as well phosphonate ester; however, in our hands these procedures
10522 J. AM. CHEM. SOC. 9 VOL. 130, NO. 32, 2008

Scheme 3. Synthesis of R-Hydroxy- and R-Aminophosphonic Acids
resulted in either no reaction or undesired side products.
Although, simple acid hydrolysis was reported to be highly
effective to generate the desired phosphonic acid.14d Attempting
to deprotect the product in methanolic concentrated HCl at room
temperature resulted in no reaction, but no loss in enantiopurity
of the original substrate is observed. However, increasing the
temperature to refluxing conditions provides the desired product
almost quantitatively (Scheme 3). Subsequent protection of the
hydroxy/amino moiety and reprotection of the acid to the methyl
phosphonates provided the fully reprotected methyl phosphonates
(see Supporting Information). We were pleased to find that no
erosion in enantioselectivity is observed during the hydrolysis
of the bis(2,2,2-trifluoroethyl) phosphonate ester moiety. Another
unique feature of this system is that, with the protected amine
in hand, both protecting groups can be removed in a single pot
with acidic hydrolysis or selective deprotection of the phosphi-
noyl moiety using mildly acidic conditions. In addition, it was
observed that the absolute configurations of the hydroxyl and
amino products were oppositely stereoconfigured, presumably
due to the single coordination of the aldehyde and the double
coordination of the aldimine to the aluminum catalyst.
In conclusion, R-hydroxy- and R-aminophosphonates were
synthesized in high yield and high enantioselectivies using low
catalyst loading (0.5 to 1 mol %) and expedient reaction times.
This is a significant improvement over other catalysts in that
they usually require higher catalyst loading, typically g5 mol
% or more and long reaction times. The ligand can be easily
recycled after purification without any loss in reactivity or
selectivity. The utility of this catalyst is currently under
investigation for other asymmetric reactions.
Acknowledgment. Support of this research was provided by
the National Science Foundation (CHE-0717618). We would like
to thank Marina Naodovic and also Dr. Ian M. Steele (X-ray
structure determination).
Supporting Information Available: Experimental procedures,
spectral data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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J. AM. CHEM. SOC. 9 VOL. 130, NO. 32, 2008 10523